Positron Emission Tomography to Elucidate Pharmacokinetic Differences of Regioisomeric Retinoid X Receptor Agonists

Kobayashi, Toshiki; Furusawa, Yuki; Yamada, Shoya; Akehi, Masaru; Takenaka, Fumiaki; Sasaki, Takanori; Akahoshi, Akiya; Hanada, Takahisa; Matsuura, Eiji; Hirano, Hiroyuki; Tai, Akihiro; Kakuta, Hiroki

doi:10.1021/ml500511m

Cited by 13 publications

(21 citation statements)

References 22 publications

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“…The novel RXR partial agonist NEt-4IB has a maximum 55% RXR efficacy compared with full agonists in a luciferase reporter gene assay, and 28 consecutive days’ administration of NEt-4IB resulted in no significant adverse events [14]. Furthermore, we have investigated the pharmacokinetics of NEt-4IB in vivo by positron emission tomography (PET) and revealed an increase in radioactivity in PET imaging of the lung [15]. …”

Section: Introductionmentioning

confidence: 99%

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma

et al. 2017

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BackgroundRetinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners—e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined.The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma.MethodsWe investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28–30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32.ResultsOral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-κB expression.ConclusionThese data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.

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Section: Introductionmentioning

confidence: 99%

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma

et al. 2017

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“…One reason for this may be the poor CNS penetration of bexarotene in human patients (~low nM range) [113]. Notably, in mice the BBB is extremely permeable to bexarotene [115]. This finding raises a general cautionary issue regarding translation of drugs from rodents to humans.…”

Section: Antisense Oligonucleotide Therapymentioning

confidence: 99%

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

Williams

Borchelt

Chakrabarty

2020

Mol Neurodegeneration

112

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One of the primary genetic risk factors for Alzheimer's disease (AD) is the presence of the Ɛ4 allele of apolipoprotein E (APOE). APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. Humans predominantly possess three different allelic variants of APOE, termed E2, E3, and E4, with the E3 allele being the most common. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE-related genetic risk, considerable effort has been devoted towards developing cellular and animal models. Data from these models indicate that APOE4 exacerbates amyloid β plaque burden in a dose-dependent manner. and may also enhance tau pathogenesis in an isoform-dependent manner. Other studies have suggested APOE4 increases the risk of AD by mechanisms that are distinct from modulation of Aβ or tau pathology. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood. Collectively, the available studies suggest that APOE may impact multiple signaling pathways and thus investigators have sought therapeutics that would disrupt pathological functions of APOE while preserving or enhancing beneficial functions. This review will highlight some of the therapeutic strategies that are currently being pursued to target APOE4 towards preventing or treating AD and we will discuss additional strategies that holds promise for the future.

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“…Molecule 39 (EC 50 = 169 nM) has antitype 2 diabetes activity with reduced side effects compared to full RXR agonists in animal models and gave a higher blood concentration than full agonist 33 , after oral administration . Kobayashi et al investigated the pharmacokinetic difference of 39 and 33 (compounds are regioisomers) by positron emission tomography (PET). PET images revealed that 39 was easily absorbed from the digestive tract and excreted slowly than 33 .…”

Section: Rxr Agonistsmentioning

confidence: 99%

“…108 Molecule 39 (EC 50 = 169 nM) has antitype 2 diabetes activity with reduced side effects compared to full RXR agonists in animal models and gave a higher blood concentration than full agonist 33, after oral administration. 108 Kobayashi et al 69 PET images revealed that 39 was easily absorbed from the digestive tract and excreted slowly than 33. The partial RXR agonist 39 may be a promising candidate for the treatment of PD and AD as well without the serious side effects caused by 2.…”

Section: Bexarotene-related Compoundsmentioning

confidence: 99%

“…63,64 The group of Zhang has identified a link between RXRα and the activation of the PI3K/AKT pathway. 65,66 Further, RXR has been associated with other diseases including leukemia, 67,68 AD, 69 schizophrenia, 70 and multiple sclerosis (MS). 71 Because of its role in gene control and non-genomic functions, the development of investigations of retinoids have attributed their actions to binding to RARs and RXRs.…”

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A review of the molecular design and biological activities of RXR agonists

Almeida

Conda‐Sheridan

2019

Medicinal Research Reviews

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An attractive approach to combat disease is to target theregulation of cell function. At the heart of this task are nuclear receptors (NRs); which control functions such as gene transcription. Arguably, the key player in this regulatory machinery is the retinoid X receptor (RXR). This NR associates with a third of the NRs found in humans. Scientists have hypothesized that controlling the activity of RXR is an attractive approach to control cellular functions that modulate diseases such as cancer, diabetes, Alzheimer's disease and Parkinson's disease. In this review, we will describe the key features of the RXR, present a historic perspective of the first RXR agonists, and discuss various templates that have been reported to activate RXR with a focus on their molecular structure, biological activity, and limitations. Finally, we will present an outlook of the field and future directions and considerations to synthesize or modulate RXR agonists to make these compounds a clinical reality.

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Positron Emission Tomography to Elucidate Pharmacokinetic Differences of Regioisomeric Retinoid X Receptor Agonists

Cited by 13 publications

References 22 publications

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma

Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

A review of the molecular design and biological activities of RXR agonists

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